The hippocampus is a brain structure that is critical for forming and retaining long-term, episodic memories. Damage to the hippocampus from Alzheimer's Disease, stroke, epilepsy, or traumatic brain injury causes a profound amnesic syndrome in which patients are unable to form lasting memories of the everyday events of their lives. Converging evidence from humans and animal models suggests that the hippocampus integrates information from two parallel processing streams, which convey information about spatial location (context) and about individual objects or items, to create conjunctive representations of objects in place (or events in context). This proposal will investigate the organization of the flow of information through these parallel processing streams into the hippocampus, as well as the interaction of these streams with intrahippocampal processing of the CA3 and CA1 regions. Prior work on hippocampal place cells of rats has demonstrated a dissociation between the hippocampal CA3 and CA1 fields in terms of the coherence of ensemble spatial representations when local cues and global landmarks are pitted against each other. CA3 demonstrated a more coherent representation than CA1, in that the place fields tended to be controlled coherently by the local cues, whereas CA1 representations split into local- and global-landmark dominated ensembles. This proposal will test a series of hypotheses regarding the anatomical flow of information into the CA3 and CA1 regions that may account for the different responses of these regions. Multi-electrode techniques will be used to record the activity of neurons in different parts of the CA3 and CA1 regions and their input structures, including the entorhinal cortex and subicular complex (parasubiculum and presubiculum) in freely behaving rats. Local and global cues sets will be altered to test whether different parts of the hippocampal formation are preferentially bound to local or global frames of reference, and whether the known anatomical projections among these areas can account for the differential responses of CA3 and CA1 ensembles to these manipulations. These experiments will generate great insight into the nature of information processing and the organization of information flow into and through the hippocampal system, information that is critical toward understanding the computations performed by the hippocampus in the service of episodic memory. Such fundamental knowledge may be crucial for devising treatment strategies to ameliorate the devastating symptoms of hippocampal amnesia and to target selective sites for potential pharmaceutical or surgical therapies for these disorders. Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's epilepsy, stroke, or traumatic injury.